Supramolecular self-assembly of amphipathic block copolymers has been utilized to generate nano- and microscale materials with controllable architectures. By controlling block and polymer characteristics including chemical composition, relative hydrophobicity and hydrophilicity, and absolute and relative block size, spherical micellar, linear fibrillar, and spherical vesicular architectures can be accessed.
Supramolecular assemblies can be created from homogeneous or heterogeneous mixtures of molecular precursors containing synthetic oligomer and polymer, polypeptide, and lipid components. A wide range of biomedical applications have been found for these soft materials; of particular interest are stimulus-responsive materials, in which changes in assembly architecture and/or biological activity are dictated by external stimuli which may include pH, redox status, or enzymatic function.
Chemical composition represents a defining characteristic of constituent molecules designed to undergo supramolecular self-assembly. In assemblies destined for biological applications, and in constituent molecules composed of synthetic polymer, the biocompatible polymer poly(ethylene glycol) (PEG) is a common component. Presentation of PEG surface chemistry to the biological environment limits recognition by phagocytes and increases material lifetime upon injection or implantation. For the preparation of block copolymer amphiphiles that yield micellar, fibrillar, and vesicular architectures upon self-assembly (Cerritelli et al., 2009), PEG-based macroinitiators have been utilized for ring-opening polymerizations of the monomer propylene sulfide.
In comparison to the spherical architecture of micellar and vesicular self-assembly architectures, linear fibrillar (or “worm-like”) structures enable a wider variety of downstream material applications and biological performance characteristics. Self-assembled materials relevant for biological applications are typically defined by presentation of a hydrophilic surface, with self-assembly at least partially driven by hydrophobic interactions and avoidance of the aqueous environment. Amphiphilic linear fibril precursors are defined by a variety of molecular components including synthetic polymers (Geng and Discher, 2005), polypeptides (Rudra et al., 2010), and peptide-lipid constructs (Hartgerink et al., 2001). Fibrillar platforms have been utilized in vivo with methodologies analogous to those optimized for micellar/vesicular platforms; for example, in the context of injectable small molecule carriers. When injected intravenously, polymer-based, hydrolysis-sensitive linear fibrils are capable of circulating in the blood as spherical materials do, but with very different circulation behaviors (Geng et al., 2007). Assembly or cross-linking of fibrillar assemblies also permits formation of bulk three-dimensional structures, for molecular depot or synthetic matrix applications. For example, Webber et al. employed assembly of pre-formed peptide-lipid amphiphiles to create dexamethasone-releasing gels (Webber et al., 2012), while Silva et al. utilized cross-linked fibril assemblies prepared from related materials for neural progenitor cell differentiation (Silva et al., 2004). The helical conformation of polyisocyanopeptides grafted with oligo(ethylene glycol) yielded thermally-responsive filamentous structures capable of extracellular matrix-mimetic hydrogel formation (Kouwer et al., 2013).
In addition to establishing defined control over the formation of self-assembled supramolecular architectures, it is valuable to define disassembly or degradation mechanisms by choice of material chemistries. A spectrum of defined control exists, ranging from relatively non-specific thermal or light sensitivity and hydrolytic susceptibility, to biologically-relevant pH or redox dependence, to highly-specific conformal or enzymatic reactivity. Previously, light sensitivity (Vasdekis et al., 2012), oxidative sensitivity (Napoli et al., 2004), and redox sensitivity (Cerritelli et al., 2007) have been explored in vesicular assemblies derived from PEG-poly(propylene sulfide). Material sensitivity to redox status in particular is relevant both in the context of inflammation in the extracellular environment and post-phagocytic lysosomal processing in the intracellular environment. Han and coworkers developed hydrogen peroxide-responsive selenium-containing polymer micelle constructs assembled from electrostatic interactions (Han et al., 2010). In another approach, Mahmoud et al. utilized emulsion solvent evaporation to prepare hydrogen peroxide-sensitive micelles for protein delivery (Mahmoud et al., 2011). Both thioketal-containing nanoparticles (Wilson et al., 2010) and thioether-containing micellar constructs (Segura and Hubbell, 2007) have been generated for intracellular siRNA delivery from oxidation-sensitive particles. Exquisite sensitivity to the biological environment has been demonstrated in nanoparticles assembled from CXCR4-derived transmembrane peptide; peptide conformational change is associated with nanoparticle disassembly and spontaneous fusion with cell membrane (Tarasov et al., 2011).